Ciliary signaling mechanisms regulating white adipose tissue expansion

调节白色脂肪组织扩张的纤毛信号机制

• 批准号: 10503649
• 负责人: Keren Hilgendorf
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-22 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503649
• 关键词: Ablation; Adipocytes; Adipose tissue; Adult; Affect; Alstrom syndrome; Architecture; Bardet-Biedl Syndrome; Biological; Body mass index; Calories; Cells; Chromatin; Cilia; Cyclic AMP; DNA Sequence Alteration; Data; Defect; Development; Diabetes Mellitus; Docosahexaenoic Acids; Equilibrium; Fatty acid glycerol esters; Female; Functional disorder; Genes; Genetic; Genetic Transcription; Goals; Health; Human; Human Genetics; Hyperplasia; Hypertrophy; Impairment; Inflammation; Insulin Resistance; Lead; Ligands; Link; Metabolic; Metabolic syndrome; Molecular; Monounsaturated Fatty Acids; Morphology; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Obesity; Omega-3 Fatty Acids; Organelles; Overweight; Pathogenesis; Pathogenicity; Patients; Polyunsaturated Fatty Acids; Proteins; Public Health; Publishing; Research; Signal Pathway; Signal Transduction; Techniques; Thinness; Tissue Differentiation; Tissue Expansion; Tissues; chromatin remodeling; ciliopathy; comorbidity; experimental study; glucose metabolism; in vivo; innovation; lipid biosynthesis; lipid metabolism; male; mouse model; novel; pandemic disease; receptor; response; tool; trafficking

Project summary: More than 70% of adults in the USA are obese or overweight, and comorbidities, such as diabetes, pose a significant challenge to public health. In response to excess nutrients, white adipose tissue expands by both hypertrophy and de novo adipogenesis. Excessive hypertrophy is linked to insulin resistance, while mechanisms that promote adipogenesis can limit the pathogenic consequences of obesity. We recently discovered that pre- adipocytes express an antenna-like signaling organelle called the primary cilium, and that primary cilia are required for in vivo adipogenesis. We propose that primary cilia function as signaling hubs in pre-adipocytes, regulating their adipogenic potential, and hence, how white adipose tissue expands in response to caloric imbalance. Remarkably, we recently discovered that pre-adipocytes isolated from obese human and murine white adipose tissue have both fewer and shorter cilia compared to lean pre-adipocytes. To elucidate the functional importance of ciliary signaling in directing how white adipose tissue expands, we propose the following two aims: (Aim 1) Investigate how obesity affects pre-adipocyte ciliation and ciliary signaling. Pre-adipocytes in obese white adipose tissue are known to differentiate poorly due to a cell-intrinsic defect that decreases their adipogenic potential. This contributes to adipocyte hypertrophy, inflammation, and tissue dysfunction. We propose that the obese white adipose tissue microenvironment promotes pathogenic loss of pre-adipocyte primary cilia. This loss results in impairment of ciliary, pro-adipogenic signaling and decreased adipogenic potential, leading to hypertrophic expansion of white adipose tissue and contributing to impairments in glucose and lipid metabolism. Using a combination of molecular and cell biological techniques and mouse models, we will define the adipogenic signaling defects governed by obesity-induced ciliary shortening and loss, as well as the underlying mechanism. (Aim 2) Determine how human genetic mutations in ciliary genes lead to obesity and diabetes. Two ciliopathies are linked to obesity in patients, but the mutations drive opposing effects with regard to metabolic health. Both ciliopathy mutations alter the trafficking of ciliary cargo into and out of the primary cilium. We propose that these alterations modulate the composition of ciliary signaling pathways, altering the adipogenic potential of pre-adipocytes and how white adipose tissue expands. Together, experiments proposed in the two aims will establish the functional importance of pre-adipocyte cilia to white adipose tissue expansion. The proposed research constitutes a completely novel and innovative approach to identifying mechanisms underlying the loss of adipogenic potential of obese pre-adipocytes that drives pathogenesis.

项目概要： 在美国，超过70%的成年人肥胖或超重，合并症，如糖尿病，构成了肥胖的主要原因。 对公共卫生的重大挑战。作为对过量营养的反应，白色脂肪组织通过两种途径扩张， 肥大和新生脂肪形成。过度肥大与胰岛素抵抗有关， 可以限制肥胖的致病后果。我们最近发现， 脂肪细胞表达一种称为初级纤毛的触角样信号细胞器，初级纤毛是 是体内脂肪生成所必需的。我们认为初级纤毛在前脂肪细胞中起着信号枢纽的作用， 调节其成脂潜力，从而调节白色脂肪组织如何响应热量而膨胀 不平衡值得注意的是，我们最近发现从肥胖的人和小鼠中分离出的前脂肪细胞 与瘦前脂肪细胞相比，白色脂肪组织具有更少和更短的纤毛。阐明本 纤毛信号传导在指导白色脂肪组织如何扩张中的功能重要性，我们提出以下建议 两个目的：（目的1）研究肥胖如何影响前脂肪细胞纤毛形成和纤毛信号传导。前脂肪细胞 已知肥胖的白色脂肪组织由于细胞内在缺陷而分化不良， 成脂潜能这有助于脂肪细胞肥大、炎症和组织功能障碍。我们 提出肥胖的白色脂肪组织微环境促进前脂肪细胞的致病性损失 初级纤毛这种损失导致纤毛、前脂肪形成信号传导的受损和脂肪形成能力的降低。 潜在的，导致白色脂肪组织的肥大性扩张，并导致葡萄糖受损 和脂质代谢。使用分子和细胞生物学技术以及小鼠模型的组合，我们 将定义由肥胖诱导的纤毛缩短和缺失所控制的脂肪形成信号缺陷，以及 潜在的机制。(Aim 2）确定人类纤毛基因的基因突变如何导致肥胖， 糖尿病两种纤毛病变与患者的肥胖有关，但突变驱动相反的效果， 代谢健康。这两种纤毛病突变都改变了纤毛货物进出原发灶的运输。 纤毛我们认为这些改变调节了纤毛信号通路的组成，改变了纤毛的结构。 前脂肪细胞的成脂潜力以及白色脂肪组织如何扩张。总之，实验提出， 在这两个目标中，将建立前脂肪细胞纤毛对白色脂肪组织扩张的功能重要性。 拟议的研究构成了一个全新的和创新的方法来确定机制 导致肥胖前脂肪细胞的成脂潜能丧失，从而导致发病。